Cyanoamino (aza)benzofuran compounds for the treatment of hepatitis C

ABSTRACT

Compounds of Formula (I), including their salts, as well as compositions and methods of using the compounds are set forth. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV: (I).

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61/968,755 filed Mar. 21, 2014, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to novel compounds, including their salts, whichhave activity against hepatitis C virus (HCV) and which are useful intreating those infected with HCV. The invention also relates tocompositions and methods of making and using these compounds.

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) is a major human pathogen, infecting anestimated 170 million persons worldwide—roughly five times the numberinfected by human immunodeficiency virus type 1. A substantial fractionof these HCV infected individuals develop serious progressive liverdisease, including cirrhosis and hepatocellular carcinoma (Lauer, G. M.;Walker, B. D. N. Engl. J. Med. 2001, 345, 41-52).

HCV is a positive-stranded RNA virus. Based on a comparison of thededuced amino acid sequence and the extensive similarity in the5′-untranslated region, HCV has been classified as a separate genus inthe Flaviviridae family. All members of the Flaviviridae family haveenveloped virions that contain a positive stranded RNA genome encodingall known virus-specific proteins via translation of a single,uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encodedamino acid sequence throughout the HCV genome. At least six majorgenotypes have been characterized, and more than 50 subtypes have beendescribed. The major genotypes of HCV differ in their distributionworldwide, and the clinical significance of the genetic heterogeneity ofHCV remains elusive despite numerous studies of the possible effect ofgenotypes on pathogenesis and therapy.

The single strand HCV RNA genome is approximately 9500 nucleotides inlength and has a single open reading frame (ORF) encoding a single largepolyprotein of about 3000 amino acids. In infected cells, thispolyprotein is cleaved at multiple sites by cellular and viral proteasesto produce the structural and non-structural (NS) proteins. In the caseof HCV, the generation of mature non-structural proteins (NS2, NS3,NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. Thefirst one is believed to be a metalloprotease and cleaves at the NS2-NS3junction; the second one is a serine protease contained within theN-terminal region of NS3 (also referred to as NS3 protease) and mediatesall the subsequent cleavages downstream of NS3, both in cis, at theNS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B,NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiplefunctions, acting as a cofactor for the NS3 protease and possiblyassisting in the membrane localization of NS3 and other viral replicasecomponents. The complex formation of the NS3 protein with NS4A seemsnecessary to the processing events, enhancing the proteolytic efficiencyat all of the sites. The NS3 protein also exhibits nucleosidetriphosphatase and RNA helicase activities. NS5B (also referred to asHCV polymerase) is a RNA-dependent RNA polymerase that is involved inthe replication of HCV. The HCV NS5B protein is described in “StructuralAnalysis of the Hepatitis C Virus RNA Polymerase in Complex withRibonucleotides (Bressanelli; S. et al., Journal of Virology 2002,3482-3492; and Defrancesco and Rice, Clinics in Liver Disease 2003, 7,211-242.

Currently, the most effective HCV therapy employs a combination ofalpha-interferon and ribavirin, leading to sustained efficacy in 40% ofpatients (Poynard, T. et al. Lancet 1998, 352, 1426-1432). Recentclinical results demonstrate that pegylated alpha-interferon is superiorto unmodified alpha-interferon as monotherapy (Zeuzem, S. et al. N.Engl. J. Med. 2000, 343, 1666-1672). However, even with experimentaltherapeutic regimens involving combinations of pegylatedalpha-interferon and ribavirin, a substantial fraction of patients donot have a sustained reduction in viral load. Thus, there is a clear andimportant need to develop effective therapeutics for treatment of HCVinfection.

HCV-796, an HCV NS5B inhibitor, has shown an ability to reduce HCV RNAlevels in patients. The viral RNA levels decreased transiently and thenrebounded during dosing when treatment was with the compound as a singleagent but levels dropped more robustly when combined with the standardof care which is a form of interferon and ribavirin. The development ofthis compound was suspended due to hepatic toxicity observed duringextended dosing of the combination regimens. U.S. Pat. No. 7,265,152 andthe corresponding PCT patent application WO2004/041201 describecompounds of the HCV-796 class. Other compounds have been disclosed; seefor example, WO2009/101022, as well as WO 2012/058125.

What is therefore needed in the art are additional compounds which arenovel and effective against hepatitis C. Additionally, these compoundsshould provide advantages for pharmaceutical uses, for example, withregard to one or more of their mechanism of action, binding, inhibitionefficacy, target selectivity, solubility, safety profiles, orbioavailability. Also needed are new formulations and methods oftreatment which utilize these compounds.

SUMMARY OF THE INVENTION

One aspect of the invention is a compound of Formula I, includingpharmaceutically acceptable salts thereof:

wherein

-   m is 0 or 1;-   R⁰, R¹ is methyl or ethyl;-   R² is phenyl that is independently substituted with 0-2 halo or    methoxy or is para substituted with W—Ar¹;-   W is —O— or —NH—;-   Ar¹ is phenyl or para-halophenyl;-   R³ is hydrogen, halo, or alkyl;-   R⁴, R⁵, R⁶, R⁷, R⁸ are each independently selected from the group of    hydrogen, halo, alkyl, cycloalkyl, haloalkyl, halocycloalkyl,    hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl,    alkoxy, hydroxyalkyloxy, alkoxyalkyloxy, Ar², COOR¹⁰¹ and    CON(R¹⁰²)(R¹⁰³);-   R¹⁰¹ is hydrogen, alkyl or cycloalkyl with 0-3 substituents selected    from the group of halo, hydroxyl, alkoxy, and haloalkoxy;-   R¹⁰², R¹⁰³ are each independently selected from the group of    hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkyl alkynyl, cyclic    ether, cyclic amine, lactame, fused bicyclic alkyl, bridged bicyclic    alkyl, spiro bicyclic alkyl, fused bicyclic ether, bridged bicyclic    ether, spiro bicyclic ether, fused bicyclic amine, bridged bicyclic    amine and spiro bicyclic amine, with 0-3 substituents selected from    the group of halo, OH, OR¹⁰⁴, NH₂, NR¹⁰⁵R¹⁰⁶, COOR¹⁰⁴, CONR¹⁰⁵R¹⁰⁶,    S(O)₂R¹⁰⁴, S(O)₂NR¹⁰⁵R¹⁰⁶, NR¹⁰⁴CONR¹⁰⁵R¹⁰⁶, OR¹⁰⁴CONR¹⁰⁵R¹⁰⁶,    C(═NR¹⁰⁷)NR¹⁰⁵R¹⁰⁶, NR¹⁰⁸C(═NR¹⁰⁷)NR¹⁰⁵R¹⁰⁶, haloalkoxy, Ar², O—Ar²,    and NR¹⁰⁵—Ar²; or-   R¹⁰² and R¹⁰³ can form a ring by joining two atoms, one from each of    R¹⁰² and R¹⁰³; or-   R¹⁰² and R¹⁰³ can form a bicyclic or tricyclic ring by joining    multiple atoms from each of R¹⁰² and R¹⁰³;-   Ar² is phenyl, 5-membered heterocyclic or 6-membered heterocyclic    ring (aromatic or nonaromatic), and is substituted with 0-3    substituents selected from the group of cyano, halo, alkyl,    cycloalkyl, haloalkyl, OH, OR¹⁰⁴, haloalkoxy, NH₂, NR¹⁰⁵R¹⁰⁶,    COOR¹⁰⁴, CONR¹⁰⁵R¹⁰⁶, S(O)₂R¹⁰⁴, S(O)₂NR¹⁰⁵R¹⁰⁶, and    NR¹⁰⁴CONR¹⁰⁵R¹⁰⁶;-   R¹⁰⁴ is hydrogen, alkyl or cycloalkyl with 0-3 substituents selected    from the group of halo, hydroxyl, alkoxy, and haloalkoxy;-   R¹⁰⁵, R¹⁰⁶ are each independently hydrogen, alkyl or cycloalkyl with    0-3 substituents selected from the group of halo, hydroxyl, alkoxy,    and haloalkoxy; or-   R¹⁰⁵ and R¹⁰⁶ can form a ring by joining two atoms, one from each of    R¹⁰⁵ and R¹⁰⁶;-   R¹⁰⁷, R¹⁰⁸ are each independently hydrogen, alkyl or cycloalkyl with    0-3 substituents selected from the group of halo, hydroxyl, alkoxy,    and haloalkoxy; or-   R¹⁰⁷ and R¹⁰⁸ can form a ring by joining two atoms, one from each of    R¹⁰⁷ and R¹⁰⁸;-   R⁹ is hydrogen, R²⁰¹, COR²⁰¹ or SO₂R²⁰¹;-   R²⁰¹ is hydrogen, alkyl or cycloalkyl with 0-3 substituents selected    from the group of halo, hydroxyl, alkoxy, haloalkoxy, phenyl and    heterocyclic;-   X is N or CR¹⁰;-   R¹⁰ is selected from the group of hydrogen, alkyl, cycloalkyl,    halogen, CN, ester, amide, 2-keto acid, 2-keto ester, 2-keo amide,    phenyl and heterocyclic, with 0-3 substituents selected from the    group of halo, hydroxyl, alkoxy, haloalkoxy, ester, amide, oxalate,    oxalamide, phenyl and heterocyclic.

The invention also relates to pharmaceutical compositions comprising acompound of Formula 1, including a pharmaceutically acceptable saltthereof , and a pharmaceutically acceptable carrier, diluent, and/orexcipient.

In addition, the invention provides one or more methods of treatinghepatitis C infection comprising administering a therapeuticallyeffective amount of a compound of Formula I to a patient.

Also provided as part of the invention are one or more methods formaking the compounds of Formula I.

The present invention is directed to these, as well as other importantends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise.

Unless otherwise specifically set forth elsewhere in the application,the following terms may be used herein and shall have the followingmeanings: “Hydrogen” or “H” refers to hydrogen, including its isotopes,such as deuterium, which may be labeled herein as “D”. “Halo” meansfluoro, chloro, bromo, or iodo. “Alkyl” means a straight or branchedalkyl group composed of 1 to 6 carbons. “Alkenyl” means a straight orbranched alkyl group composed of 2 to 6 carbons with at least one doublebond. “Cycloalkyl” means a monocyclic ring system composed of 3 to 7carbons. “Hydroxyalkyl,” “alkoxy” and other terms with a substitutedalkyl moiety include straight and branched isomers composed of 1 to 6carbon atoms for the alkyl moiety. “Halo” includes all halogenatedisomers from monohalo substituted to perhalo substituted in substituentsdefined with halo, for example, “Haloalkyl” and “haloalkoxy”,“halophenyl”, “halophenoxy.” “Aryl” means a monocyclic or bicyclicaromatic hydrocarbon groups having 6 to 12 carbon atoms, or a bicyclicfused ring system wherein one or both of the rings is a phenyl group.Bicyclic fused ring systems consist of a phenyl group fused to a four-to six-membered aromatic or non-aromatic carbocyclic ring.Representative examples of aryl groups include, but are not limited to,indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. “Heteroaryl”means a 5 to 7 membered monocyclic or 8 to 11 membered bicyclic aromaticring system with 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur. Parenthetic and multiparenthetic terms are intendedto clarify bonding relationships to those skilled in the art. Forexample, a term such as ((R)alkyl) means an alkyl substituent furthersubstituted with the substituent R. Substituents which are illustratedby chemical drawing to bond at variable positions on a multiple ringsystem (for example a bicyclic ring system) are intended to bond to thering where they are drawn to append.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,camsylate, chloride, citrate, fumarate, glucouronate, hydrobromide,hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate,pamoate, phosphate, succinate, sulfate, tartrate, tosylate, andxinofoate. Some cationic salt forms include ammonium, aluminum,benzathine, bismuth, calcium, choline, diethylamine, diethanolamine,lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine,potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention possess asymmetric carbon atoms.The invention includes all stereoisomeric forms, including enantiomersand diastereomers as well as mixtures of stereoisomers such asracemates. Some stereoisomers can be made using methods known in theart. Stereoisomeric mixtures of the compounds and related intermediatescan be separated into individual isomers according to methods commonlyknown in the art. The use of wedges or hashes in the depictions ofmolecular structures in the following schemes and tables is intendedonly to indicate relative stereochemistry, and should not be interpretedas implying absolute stereochemical assignments.

The invention is intended to include all isotopes of atoms occurring inthe present compounds. Isotopes include those atoms having the sameatomic number but different mass numbers. By way of general example andwithout limitation, isotopes of hydrogen include deuterium and tritium.Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compoundsof the invention can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed herein, using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent otherwise employed. Such compounds mayhave a variety of potential uses, for example as standards and reagentsin determining biological activity. In the case of stable isotopes, suchcompounds may have the potential to favorably modify biological,pharmacological, or pharmacokinetic properties.

The invention is also intended to encompass prodrugs of the compoundsherein.

As set forth above, the invention is directed to one or more compoundsof Formula I, including pharmaceutically acceptable salts thereof:

wherein

-   m is 0 or 1;-   R⁰, R¹ is methyl or ethyl;-   R² is phenyl that is independently substituted with 0-2 halo or    methoxy or is para substituted with W—Ar¹;-   W is —O— or —NH—;-   Ar¹ is phenyl or para-halophenyl;-   R³ is hydrogen, halo, or alkyl;-   R⁴, R⁵, R⁶, R⁷, R⁸ are each independently selected from the group of    hydrogen, halo, alkyl, cycloalkyl, haloalkyl, halocycloalkyl,    hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl,    alkoxy, hydroxyalkyloxy, alkoxyalkyloxy, Ar², COOR¹⁰¹ and    CON(R¹⁰²)(R¹⁰³);-   R¹⁰¹ is hydrogen, alkyl or cycloalkyl with 0-3 substituents selected    from the group of halo, hydroxyl, alkoxy, and haloalkoxy;-   R¹⁰², R¹⁰³ are each independently selected from the group of    hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkyl alkynyl, cyclic    ether, cyclic amine, lactame, fused bicyclic alkyl, bridged bicyclic    alkyl, spiro bicyclic alkyl, fused bicyclic ether, bridged bicyclic    ether, spiro bicyclic ether, fused bicyclic amine, bridged bicyclic    amine and spiro bicyclic amine, with 0-3 substituents selected from    the group of halo, OH, OR¹⁰⁴, NH₂, NR¹⁰⁵R¹⁰⁶, COOR¹⁰⁴, CONR¹⁰⁵R¹⁰⁶,    S(O)₂R¹⁰⁴, S(O)₂NR¹⁰⁵R¹⁰⁶, NR¹⁰⁴CONR¹⁰⁵R¹⁰⁶, OR¹⁰⁴CONR¹⁰⁵R¹⁰⁶,    C(═NR¹⁰⁷)NR¹⁰⁵R¹⁰⁶, NR¹⁰⁸C(═NR¹⁰⁷)NR¹⁰⁵R¹⁰⁶, haloalkoxy, Ar², O—Ar²,    and NR¹⁰⁵—Ar²; or-   R¹⁰² and R¹⁰³ can form a ring by joining two atoms, one from each of    R¹⁰² and R¹⁰³; or-   R¹⁰² and R¹⁰³ can form a bicyclic or tricyclic ring by joining    multiple atoms from each of R¹⁰² and R¹⁰³;-   Ar² is phenyl, 5-membered heterocyclic or 6-membered heterocyclic    ring (aromatic or nonaromatic), and is substituted with 0-3    substituents selected from the group of cyano, halo, alkyl,    cycloalkyl, haloalkyl, OH, OR¹⁰⁴, haloalkoxy, NH₂, NR¹⁰⁵R¹⁰⁶,    COOR¹⁰⁴, CONR¹⁰⁵R¹⁰⁶, S(O)₂R¹⁰⁴, S(O)₂NR¹⁰⁵R¹⁰⁶, and    NR¹⁰⁴CONR¹⁰⁵R¹⁰⁶;-   R¹⁰⁴ is hydrogen, alkyl or cycloalkyl with 0-3 substituents selected    from the group of halo, hydroxyl, alkoxy, and haloalkoxy;-   R¹⁰⁵, R¹⁰⁶ are each independently hydrogen, alkyl or cycloalkyl with    0-3 substituents selected from the group of halo, hydroxyl, alkoxy,    and haloalkoxy; or-   R¹⁰⁵ and R¹⁰⁶ can form a ring by joining two atoms, one from each of    R¹⁰⁵ and R¹⁰⁶;-   R¹⁰⁷, R¹⁰⁸ are each independently hydrogen, alkyl or cycloalkyl with    0-3 substituents selected from the group of halo, hydroxyl, alkoxy,    and haloalkoxy; or-   R¹⁰⁷ and R¹⁰⁸ can form a ring by joining two atoms, one from each of    R¹⁰⁷ and R¹⁰⁸;-   R⁹ is hydrogen, R²⁰¹, COR²⁰¹ or SO₂R²⁰¹;-   R²⁰¹ is hydrogen, alkyl or cycloalkyl with 0-3 substituents selected    from the group of halo, hydroxyl, alkoxy, haloalkoxy, phenyl and    heterocyclic;-   X is N or CR¹⁰;-   R¹⁰ is selected from the group of hydrogen, alkyl, cycloalkyl,    halogen, CN, ester, amide, 2-keto acid, 2-keto ester, 2-keo amide,    phenyl and heterocyclic with 0-3 substituents selected from the    group of halo, hydroxyl, alkoxy, haloalkoxy, ester, amide, oxalate,    oxalamide, phenyl and heterocyclic.

In a preferred embodiment of the invention, m is 0.

It is also preferred that R² is phenyl which is substituted with 1 halogroup, more preferably a fluoro group.

Additionally, it is preferred that each of R⁴, R⁵, R⁶, R⁷, R⁸, and morepreferably R⁷, is selected from CON(R¹⁰²)R¹⁰³).

In certain embodiments it is also preferred that R¹⁰², R¹⁰³ are eachselected from hydrogen, alkyl and cycloalkyl. Even more preferably, thealkyl and cycloalkyl groups are further substituted.

It is also preferred herein that R⁹ is alkyl, and more preferably ethyl.

Further preferred is the embodiment wherein m is 0, R² is phenyl whichis para-substituted with one fluoro group, R⁷ is selected fromCON(R¹⁰²)(R¹⁰³), and each of R¹⁰², R¹⁰³ is selected from hydrogen, alkyland cycloalkyl, such that the alkyl and cycloalkyl groups are furthersubstituted.

Also preferred are compounds, including pharmaceutically acceptablesalts thereof, which are selected from the group of:

In addition, the following compounds, including pharmaceuticallyacceptable salts thereof, which are selected from the group of

are also preferred herein.

Pharmaceutical Compositions and Methods of Treatment

The compounds according to the various embodiments herein set forthdemonstrate activity against HCV NS5B, and can be useful in treating HCVand HCV infection. Therefore, another aspect of the invention is acomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,diluent and/or excipient.

Another aspect of the invention is a composition further comprising anadditional compound having anti-HCV activity.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is an interferon or a ribavirin. Another aspectof the invention is wherein the interferon is selected from interferonalpha 2B, pegylated interferon alpha, consensus interferon, interferonalpha 2A, interferon lambda, and lymphoblastoid interferon tau.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is a cyclosporin. Another aspect of theinvention is where the cyclosporin is cyclosporin A.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is selected from the group consisting ofinterleukin 2, interleukin 6, interleukin 12, a compound that enhancesthe development of a type 1 helper T cell response, interfering RNA,anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospatedehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is effective to inhibit the function of atarget selected from HCV metalloprotease, HCV serine protease, HCVpolymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCVegress, HCV NS5A protein, IMPDH, and a nucleoside analog for thetreatment of an HCV infection.

Another aspect of the invention is a composition comprising a compoundof Formula I, or a pharmaceutically acceptable salt thereof, apharmaceutically acceptable carrier, an interferon and ribavirin.

Another aspect of the invention is a method of inhibiting the functionof the HCV replicon comprising contacting the HCV replicon with acompound of Formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of inhibiting the functionof the HCV NS5B protein comprising contacting the HCV NS5B protein witha compound of Formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of treating an HCV infectionin a patient comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof. In another embodiment the compound is effectiveto inhibit the function of the HCV replicon. In another embodiment thecompound is effective to inhibit the function of the HCV NS5B protein.

Another aspect of the invention is a method of treating an HCV infectionin a patient comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, in conjunction with (prior to, after, orconcurrently) another compound having anti-HCV activity.

Another aspect of the invention is the method wherein the other compoundhaving anti-HCV activity is an interferon or a ribavirin.

Another aspect of the invention is the method where the interferon isselected from interferon alpha 2B, pegylated interferon alpha, consensusinterferon, interferon alpha 2A, interferon lambda, and lymphoblastoidinterferon tau.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is a cyclosporin.

Another aspect of the invention is the method where the cyclosporin iscyclosporin A.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is selected from interleukin 2, interleukin 6,interleukin 12, a compound that enhances the development of a type 1helper T cell response, interfering RNA, anti-sense RNA, Imiqimod,ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor,amantadine, and rimantadine.

Another aspect of the invention is the method wherein the other compoundhaving anti-HCV activity is effective to inhibit the function of atarget selected from the group consisting of HCV metalloprotease, HCVserine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCVentry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and anucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is the method wherein the other compoundhaving anti-HCV activity is effective to inhibit the function of targetin the HCV life cycle other than the HCV NS5B protein.

“Therapeutically effective” means the amount of agent required toprovide a meaningful patient benefit as understood by practitioners inthe field of hepatitis and HCV infection.

“Patient” means a person infected with the HCV virus and suitable fortherapy as understood by practitioners in the field of hepatitis and HCVinfection.

“Treatment,” “therapy,” “regimen,” “HCV infection,” and related termsare used as understood by practitioners in the field of hepatitis andHCV infection.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound or its pharmaceutically acceptable salt and a pharmaceuticallyacceptable carrier and may contain conventional excipients.Pharmaceutically acceptable carriers are those conventionally knowncarriers having acceptable safety profiles. Compositions encompass allcommon solid and liquid forms including for example capsules, tablets,lozenges, and powders as well as liquid suspensions, syrups, elixers,and solutions. Compositions are made using common formulationtechniques, and conventional excipients (such as binding and wettingagents) and vehicles (such as water and alcohols) are generally used forcompositions. See, for example, Remington's Pharmaceutical Sciences,Mack Publishing Company, Easton, Pa., 17th edition, 1985.

Solid compositions are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be presentin a unit range similar to agents of that class used clinically.Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of 1-100 mg/mL. Someexamples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100mg/mL. Generally, other agents will be present in a unit range similarto agents of that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other agents used clinically. Typically, the daily dosewill be 1-100 mg/kg body weight daily. Generally, more compound isrequired orally and less parenterally. The specific dosing regimen,however, will be determined by a physician using sound medical judgment.

The invention also encompasses methods where the compound is given incombination therapy. That is, the compound can be used in conjunctionwith, but separately from, other agents useful in treating hepatitis andHCV infection. In these combination methods, the compound will generallybe given in a daily dose of 1-100 mg/kg body weight daily in conjunctionwith other agents. The other agents generally will be given in theamounts used therapeutically. The specific dosing regimen, however, willbe determined by a physician using sound medical judgment.

Some examples of compounds suitable for compositions and methods arelisted in Table 1.

TABLE 1 Physiolog- Type of Inhibitor Brand Name ical Class or TargetSource Company NIM811 Cyclophilin Novartis Inhibitor Zadaxin Immuno-Sciclone modulator Suvus Methylene blue Bioenvision Actilon TLR9 agonistColey (CPG10101) Batabulin Anticancer β-tubulin Tularik Inc., South(T67) inhibitor San Francisco, CA ISIS 14803 Antiviral antisense ISISPharmaceuticals Inc, Carlsbad, CA/Elan Phamaceuticals Inc., New York, NYSummetrel Antiviral antiviral Endo Pharmaceuticals Holdings Inc., ChaddsFord, PA GS-9132 Antiviral HCV Achillion/Gilead (ACH-806) InhibitorPyrazolo- Antiviral HCV Arrow Therapeutics pyrimidine Inhibitors Ltd.compounds and salts From WO- 2005047288 26 May 2005 Levovirin AntiviralIMPDH Ribapharm Inc., inhibitor Costa Mesa, CA Merimepodib AntiviralIMPDH Vertex (VX-497) inhibitor Pharmaceuticals Inc., Cambridge, MAXTL-6865 Antiviral monoclonal XTL Bio- (XTL-002) antibodypharmaceuticals Ltd., Rehovot, Israel Telaprevir Antiviral NS3 Vertex(VX-950, serine protease Pharmaceuticals LY-570310) inhibitor Inc.,Cambridge, MA/Eli Lilly and Co. Inc., Indianapolis, IN HCV-796 AntiviralNS5B Replicase Wyeth/Viropharma Inhibitor NM-283 Antiviral NS5BReplicase Idenix/Novartis Inhibitor GL-59728 Antiviral NS5B ReplicaseGene Labs/ Inhibitor Novartis GL-60667 Antiviral NS5B Replicase GeneLabs/ Inhibitor Novartis 2′C MeA Antiviral NS5B Replicase GileadInhibitor PSI 6130 Antiviral NS5B Replicase Roche Inhibitor R1626Antiviral NS5B Replicase Roche Inhibitor 2′C Methyl Antiviral NS5BReplicase Merck adenosine Inhibitor JTK-003 Antiviral RdRp Japan TobaccoInc., inhibitor Tokyo, Japan Levovirin Antiviral ribavirin ICNPharmaceuticals, Costa Mesa, CA Ribavirin Antiviral ribavirinSchering-Plough Corporation, Kenilworth, NJ Viramidine AntiviralRibavirin Ribapharm Inc., Prodrug Costa Mesa, CA Heptazyme Antiviralribozyme Ribozyme Pharmaceuticals Inc., Boulder, CO BILN-2061 Antiviralserine protease Boehringer inhibitor Ingelheim Pharma KG, Ingelheim,Germany SCH 503034 Antiviral serine protease Schering Plough inhibitorZadazim Immune Immune SciClone modulator modulator Pharmaceuticals Inc.,San Mateo, CA Ceplene Immuno- immune Maxim modulator modulatorPharmaceuticals Inc., San Diego, CA CellCept Immuno- HCV IgG F.Hoffmann-La suppressant immuno- Roche LTD, Basel, suppressantSwitzerland Civacir Immuno- HCV IgG Nabi Bio- suppressant immuno-pharmaceuticals suppressant Inc., Boca Raton, FL Albuferon - αInterferon albumin Human Genome IFN-α2b Sciences Inc., Rockville, MDInfergen A Interferon IFN InterMune alfacon-1 Pharmaceuticals Inc.,Brisbane, CA Omega IFN Interferon IFN-ω Intarcia Therapeutics IFN-β andInterferon IFN-β and Transition EMZ701 EMZ701 Therapeutics Inc.,Ontario, Canada Rebif Interferon IFN-β1a Serono, Geneva, SwitzerlandRoferon A Interferon IFN-α2a F. Hoffmann-La Roche LTD, Basel,Switzerland Intron A Interferon IFN-α2b Schering-Plough Corporation,Kenilworth, NJ Intron A Interferon IFN-α2b/ RegeneRx and α1-thymosinBiopharma. Inc., Zadaxin Bethesda, MD/ SciClone Pharmaceuticals Inc, SanMateo, CA Rebetron Interferon IFN-α2b/ Schering-Plough ribavirinCorporation, Kenilworth, NJ Actimmune Interferon INF-γ InterMune Inc.,Brisbane, CA Interferon-β Interferon Interferon-β-1a Serono MultiferonInterferon Long lasting Viragen/ IFN Valentis Wellferon InterferonLympho-blastoid GlaxoSmithKline IFN-αn1 plc, Uxbridge, UK OmniferonInterferon natural IFN-α Viragen Inc., Plantation, FL Pegasys InterferonPEGylated F. Hoffmann-La IFN-α2a Roche LTD, Basel, Switzerland Pegasysand Interferon PEGylated Maxim Ceplene IFN-α2a/ Pharmaceuticals immuneInc., San Diego, CA modulator Pegasys and Interferon PEGylated F.Hoffmann-La Ribavirin IFN-α2a/ Roche LTD, Basel, ribavirin SwitzerlandPEG-Intron Interferon PEGylated Schering-Plough IFN-α2b Corporation,Kenilworth, NJ PEG-Intron/ Interferon PEGylated Schering-PloughRibavirin IFN-α2b/ Corporation, ribavirin Kenilworth, NJ IP-501 Liverantifibrotic Indevus protection Pharmaceuticals Inc., Lexington, MAIDN-6556 Liver caspase Idun protection inhibitor Pharmaceuticals Inc.,San Diego, CA ITMN-191 Antiviral serine protease InterMune (R-7227)inhibitor Pharmaceuticals Inc., Brisbane, CA GL-59728 Antiviral NS5BReplicase Genelabs Inhibitor ANA-971 Antiviral TLR-7 agonist AnadysBoceprevir Antiviral serine protease Schering Plough inhibitor TMS-435Antiviral serine protease Tibotec BVBA, inhibitor Mechelen, BelgiumBI-201335 Antiviral serine protease Boehringer inhibitor IngelheimPharma KG, Ingelheim, Germany MK-7009 Antiviral serine protease Merckinhibitor PF-00868554 Antiviral replicase Pfizer inhibitor ANA598Antiviral Non-Nucleoside Anadys NS5B Polymerase Pharmaceuticals,Inhibitor Inc., San Diego, CA, USA IDX375 Antiviral Non-NucleosideIdenix Replicase Pharmaceuticals, Inhibitor Cambridge, MA, USA BILB 1941Antiviral NS5B Polymerase Boehringer Inhibitor Ingelheim Canada Ltd R&D,Laval, QC, Canada PSI-7851 Antiviral Nucleoside Pharmasset, PolymerasePrinceton, NJ, USA Inhibitor PSI-7977 Antiviral Nucleotide NS5BPharmasset, Polymerase Princeton, NJ, USA Inhibitor VCH-759 AntiviralNS5B Polymerase ViroChem Pharma Inhibitor VCH-916 Antiviral NS5BPolymerase ViroChem Pharma Inhibitor GS-9190 Antiviral NS5B PolymeraseGilead Inhibitor Peg-interferon Antiviral InterferonZymoGenetics/Bristol- lambda Myers Squibb

Synthesis Methods

The compounds may be made by methods known in the art, including thosedescribed below. Some reagents and intermediates are known in the art.Other reagents and intermediates can be made by methods known in the artusing commercially available materials. The variables (e.g. numbered “R”substituents) used to describe the synthesis of the compounds areintended only to illustrate how to make and are not to be confused withvariables used in the claims or in other sections of the specification.Abbreviations used within the schemes generally follow conventions usedin the art.

Abbreviations used in the schemes generally follow conventions used inthe art. Chemical abbreviations used in the specification and examplesare defined as follows: “NaHMDS” for sodium bis(trimethylsilyl)amide;“DMF” for N,N-dimethylformamide; “MeOH” for methanol; “NBS” forN-bromosuccinimide; “Ar” for aryl; “TFA” for trifluoroacetic acid; “LAH”for lithium aluminum hydride; “DMSO” for dimethylsulfoxide; “h” forhours; “rt” for room temperature or retention time (context willdictate); “min” for minutes; “EtOAc” for ethyl acetate; “THF” fortetrahydrofuran; “EDTA” for ethylenediaminetetraacetic acid; “Et₂O” fordiethyl ether; “DMAP” for 4-dimethylaminopyridine; “DCE” for1,2-dichloroethane; “ACN” for acetonitrile; “DME” for1,2-dimethoxyethane; “HOBt” for 1-hydroxybenzotriazole hydrate; “DIEA”for diisopropylethylamine

For the section of compounds in the 0000 series all LiquidChromatography (LC) data were recorded on a Shimadzu LC-10AS or LC-20ASliquid chromotograph using a SPD-10AV or SPD-20A UV-Vis detector andMass Spectrometry (MS) data were determined with a Micromass Platformfor LC in electrospray mode.

HPLC Method (i.e., compound isolation). Compounds purified bypreparative HPLC were diluted in methanol (1.2 mL) and purified using aShimadzu LC-8A or LC-10A or Dionex APS-3000 or Waters Acquity™ automatedpreparative HPLC system.

EXAMPLES Preparation of Compounds 1001:

iPr₂NEt (0.25 mL) and BrCN were added into a solution of6-(ethylamino)-2-(4-fluorophenyl)-N-methyl-5-(3-((2-methyl-2-phenylpropyl)carbamoyl)phenyl)benzofuran-3-carboxamide(8 mg) in THF (1 mL). The reaction was stirred at 85° C. for 24 hours.The product was isolated by preparative HPLC system.

1001 MS (M − H)⁺ Calcd. 589.3 MS (M − H)⁺ Observ. 589.3 Retention Time2.28 min LC Condition Solvent A 90% Water -10% Methanol-0.1% TFA SolventB 10% Water -90% Methanol-0.1% TFA Start % B 0 Final % B 100 GradientTime 2 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair Water -Methanol- TFA Column PHENOMENEX-LUNA 2.0 × 30 mm 3 umCompounds 1002-1011 and 1013-1017 were prepared via the same proceduretowards compound 1001, using the corresponding amines as the startingmaterials. LC condition for compounds 1002-1011 and 1013-1017 was thesame for compound 1001.

MS MS Retention Cmpd (M + H)⁺ (M + H)⁺ Time # Structure Calcd. Observ.(min) 1002

689.2 689.2 2.34 1003

597.2 597.3 2.19 1004

557.3 557.3 2.17 1005

529.2 529.2 2.09 1006

543.2 543.3 2.19 1007

524.2 524.2 2.02 1008

580.2 580.2 2.10 1009

593.2 593.2 2.05 1010

565.2 565.1 2.14 1011

545.2 545.2 1.86 1013

575.2 575.2 2.03 1014

582.2 582.2 2.14 1015

536.2 536.2 2.04 1016

557.2 557.2 2.10 1017

552.3 552.3 2.19

Preparation of Compound 1012:

iPr₂NEt (0.25 mL) and BrCN were added into a solution of5-(3-((1-(dimethylamino)-2-methyl-1-oxopropan-2-yl)carbamoyl)phenyl)-6-(ethylamino)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(8 mg) in THF (1 mL). The reaction was stirred at 85° C. for 24 hours.The product was isolated by preparative HPLC system.

1012 MS (M − H)⁺ Calcd. 525.2 MS (M − H)⁺ Observ. 525.2 Retention Time2.02 min LC Condition Solvent A 90% Water -10% Methanol-0.1% TFA SolventB 10% Water -90% Methanol-0.1% TFA Start % B 0 Final % B 100 GradientTime 2 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair Water -Methanol- TFA Column PHENOMENEX-LUNA 2.0 × 30 mm 3 um

Biological Methods

The compound demonstrated activity against HCV NS5B as determined in thefollowing HCV RdRp assays.

HCV NS5B RdRp cloning, expression, and purification. The cDNA encodingNS5B proteins of HCV genotype 1b (Con1), a genotype 1b variant withamino acid 316 mutated from cysteine to asparagine, and genotype 2a(JFH-1), were cloned into the pET21a expression vector. Each untaggedprotein was expressed with an 18 amino acid C-terminal truncation toenhance the solubility. The E. coli competent cell line BL21(DE3) wasused for expression of the protein. Cultures were grown at 37° C. for ˜4hours until the cultures reached an optical density of 2.0 at 600 nm.The cultures were cooled to 20° C. and induced with 1 mM IPTG. Freshampicillin was added to a final concentration of 50 μg/mL and the cellswere grown overnight at 20° C.

Cell pellets (3L) were lysed for purification to yield 15-24 mgs ofpurified NS5B. The lysis buffer consisted of 20 mM Tris-HCl, pH 7.4, 500mM NaCl, 0.5% triton X-100, 1 mM DTT, 1 mM EDTA, 20% glycerol, 0.5 mg/mLlysozyme, 10 mM MgCl₂, 15 ug/mL deoxyribonuclease I, and Complete TMprotease inhibitor tablets (Roche). After addition of the lysis buffer,frozen cell pellets were resuspended using a tissue homogenizer. Toreduce the viscosity of the sample, aliquots of the lysate weresonicated on ice using a microtip attached to a Branson sonicator. Thesonicated lysate was centrifuged at 100,000×g for 30 minutes at 4° C.and filtered through a 0.2 μm filter unit (Corning).

The protein was purified using two sequential chromatography steps:Heparin sepharose CL-6B and polyU sepharose 4B. The chromatographybuffers were identical to the lysis buffer but contained no lysozyme,deoxyribonuclease I, MgCl₂ or protease inhibitor and the NaClconcentration of the buffer was adjusted according to the requirementsfor charging the protein onto the column. Each column was eluted with aNaCl gradient which varied in length from 5-50 column volumes dependingon the column type. After the final chromatography step, the resultingpurity of the enzyme is >90% based on SDS-PAGE analysis. The enzyme wasaliquoted and stored at −80° C.

HCV NS5B RdRp enzyme assay. An on-bead solid phase homogeneous assay wasused in a 384-well format to assess NS5B inhibitors (Wang Y-K, Rigat K,Roberts S, and Gao M (2006) Anal Biochem, 359: 106-111). Thebiotinylated oligo dT₁₂ primer was captured on streptavidin-coupledimaging beads (GE, RPNQ0261) by mixing primer and beads in 1× buffer andincubating at room temperature for three hours. Unbound primer wasremoved after centrifugation. The primer-bound beads were resuspended in3× reaction mix (20 mM Hepes buffer, pH 7.5, dT primer coupled beads,poly A template, ³H-UTP, and RNAse inhibitor (Promega N2515)). Compoundswere serially diluted 1:3 in DMSO and aliquoted into assay plates. Equalvolumes (5 μL) of water, 3× reaction mix, and enzyme in 3× assay buffer(60 mM Hepes buffer, pH 7.5, 7.5 mM MgCl₂, 7.5 mM KCl, 3 mM DTT, 0.03mg/mL BSA, 6% glycerol) were added to the diluted compound on the assayplate. Final concentration of components in 384-well assay: 0.36 nMtemplate, 15 nM primer, 0.29 μM ³H-UTP (0.3 μCi), 1.6 U/μL RNAseinhibitor, 7 nM NS5B enzyme, 0.01 mg/mL BSA, 1 mM DTT, and 0.33 μg/μLbeads, 20 mM Hepes buffer, pH 7.5, 2.5 mM MgCl₂, 2.5 mM KCl, and 0.1%DMSO.

Reactions were allowed to proceed for 24 hours at 30° C. and terminatedby the addition of 50 mM EDTA (5 μL). After incubating for at least 15minutes, plates were read on an Amersham LEADseeker multimodalityimaging system.

IC₅₀ values for compounds were determined using ten different [I]. IC₅₀values were calculated from the inhibition using the four-parameterlogistic formula y=A+((B-A)/(1+((C/x)^D))), where A and B denote minimaland maximal % inhibition, respectively, C is the IC₅₀, D is hill slopeand x represents compound concentration.

Cell lines. The cell lines used to evaluate compounds consist of a humanhepatocyte derived cell line (Huh-7) that constitutively expresses agenotype 1b (Con-1) HCV replicon or a genotype 1b (Con-1) HCV repliconwith an asparagine replacing the cysteine at amino acid 316, or agenotype 2a (JFH-1) replicon, containing a Renilla luciferase reportergene. These cells were maintained in Dulbecco's modified Eagle medium(DMEM) containing 10% FBS, 100 U/mL penicillin/streptomycin and 1.0mg/mL G418.

HCV replicon luciferase assay. To evaluate compound efficacy, titratedcompounds were transferred to sterile 384-well tissue culture treatedplates, and the plates were seeded with HCV replicon cells (50 μL at adensity of 2.4×10³ cells/well) in DMEM containing 4% FBS (final DMSOconcentration at 0.5%). After 3 days incubation at 37° C., cells wereanalyzed for Renilla Luciferase activity using the EnduRen substrate(Promega cat #E6485) according to the manufacturer's directions.Briefly, the EnduRen substrate was diluted in DMEM and then added to theplates to a final concentration of 7.5 μM. The plates were incubated forat least 1 h at 37° C. then read on a Viewlux Imager (PerkinElmer) usinga luminescence program. The 50% effective concentration (EC₅₀) wascalculated using the four-parameter logistic formula noted above.

To assess cytotoxicity of compounds, Cell Titer-Blue (Promega) was addedto the EnduRen-containing plates and incubated for at least 4 hrs at 37°C. The fluorescence signal from each well was read using a ViewluxImager. All CC₅₀ values were calculated using the four-parameterlogistic formula.

Compound EC₅₀ data is expressed as A: <100 nM; B=100-1000 nM; C>1000nM). Representative data for compounds are reported in Table 2.

TABLE 2 EC₅₀ (μM) Cmpd# Structure 1b 1001

A 1002

0.047  A 1003

A 1004

0.013  A 1005

A 1006

A 1007

0.0041 A 1008

A 1009

A 1010

A 1011

B 1012

0.36  B 1013

A 1014

A 1015

A 1016

A 1017

0.0039 A

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

We claim:
 1. A compound of Formula I, including a pharmaceutically acceptable salts thereof:

wherein R⁰ is hydrogen, methyl or ethyl; R¹ is methyl or ethyl; R² is phenyl that is independently substituted with 0-2 halo or methoxy or is para substituted with W—Ar¹; W is —O— or —NH—; Ar¹ is phenyl or para-halophenyl; R³ is hydrogen, halo, or alkyl; R⁴, R⁵, R⁶, R⁷, R⁸ are each independently selected from the group of hydrogen, halo, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, alkoxy, hydroxyalkyloxy, alkoxyalkyloxy, Ar², COOR¹⁰¹ and CON(R¹⁰²)(R¹⁰³); R¹⁰¹ is hydrogen, alkyl or cycloalkyl with 0-3 substituents selected from the group of halo, hydroxyl, alkoxy, and haloalkoxy; R¹⁰², R¹⁰³ are each independently selected from the group of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkyl alkynyl, cyclic ether, cyclic amine, lactame, fused bicyclic alkyl, bridged bicyclic alkyl, spiro bicyclic alkyl, fused bicyclic ether, bridged bicyclic ether, spiro bicyclic ether, fused bicyclic amine, bridged bicyclic amine and spiro bicyclic amine, with 0-3 substituents selected from the group of halo, OH, OR¹⁰⁴, NH₂, NR¹⁰⁵R¹⁰⁶, COOR¹⁰⁴, CONR¹⁰⁵R¹⁰⁶, S(O)₂R¹⁰⁴, S(O)₂NR¹⁰⁵R¹⁰⁶, NR¹⁰⁴CONR¹⁰⁵R¹⁰⁶, OR¹⁰⁴CONR¹⁰⁵R¹⁰⁶, C(═NR¹⁰⁷)NR¹⁰⁵R¹⁰⁶, NR¹⁰⁸C(═NR¹⁰⁷)NR¹⁰⁵R¹⁰⁶, haloalkoxy, Ar², O—Ar², and NR¹⁰⁵—Ar²; or R¹⁰² and R¹⁰³ can form a ring by joining two atoms, one from each of R¹⁰² and R¹⁰³; or R¹⁰² and R¹⁰³ can form a bicyclic or tricyclic ring by joining multiple atoms from each R¹⁰² and R¹⁰³; Ar² is phenyl, 5-membered heteroaromatic or 6-membered heteraromatic ring, and is substituted with 0-3 substituents selected from the group of cyano, halo, alkyl, cycloalkyl, haloalkyl, OH, OR¹⁰⁴, haloalkoxy, NH₂, NR¹⁰⁵R¹⁰⁶, COOR¹⁰⁴, CONR¹⁰⁵R¹⁰⁶, S(O)₂R¹⁰⁴, S(O)₂NR¹⁰⁵R¹⁰⁶, and NR¹⁰⁴CONR¹⁰⁵R¹⁰⁶; R¹⁰⁴ is hydrogen, alkyl or cycloalkyl with 0-3 substituents selected from the group of halo, hydroxyl, alkoxy, and haloalkoxy; R¹⁰⁵ and R¹⁰⁶ are each independently hydrogen, alkyl or cycloalkyl with 0-3 substituents selected from the group of halo, hydroxyl, alkoxy, and haloalkoxy; or R¹⁰⁵ and R¹⁰⁶ can form a ring by joining two atoms, one from each of R¹⁰⁵ and R¹⁰⁶; R¹⁰⁷ and R¹⁰⁸ are each independently hydrogen, alkyl or cycloalkyl with 0-3 substituents selected from the group of halo, hydroxyl, alkoxy, and haloalkoxy; or R¹⁰⁷ and R¹⁰⁸ can form a ring by joining two atoms, one from each of R¹⁰⁷ and R¹⁰⁸; R⁹ is hydrogen, R²⁰¹, COR²⁰¹ or SO₂R²⁰¹; R²⁰¹ is hydrogen, alkyl or cycloalkyl with 0-3 substituents selected from the group of halo, hydroxyl, alkoxy, haloalkoxy, phenyl and heterocyclic; X is N or CR¹⁰; and R¹⁰ is hydrogen or alkyl.
 2. A compound of claim 1 wherein R² is phenyl which is substituted with 1 halo group.
 3. A compound of claim 1 wherein R⁷ is CON(R¹⁰²)(R¹⁰³).
 4. A compound of claim 3, wherein R¹⁰² and R¹⁰³ are each selected from hydrogen, alkyl and cycloalkyl.
 5. A compound including a pharmaceutically acceptable salt thereof, which is selected from the group of:


6. A composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent and/or excipient.
 7. A method of treating hepatitis C infection comprising administering a therapeutically effective amount of a compound of claim 1 to a patient. 